Autism is a severe developmental disorder afflicting about 2-10 per 10,000 individuals. While twin and family studies support significant gene involvement, the specific mode of genetic inheritance is unknown and multiplicative gene action, genetic heterogeneity, and variable expression of underlying susceptibility genes are probable. Given the unknown and complex mode of genetic inheritance in autism, success in localizing underlying disease genes in autism will require evaluation of hundreds of genetic markers spanning the genome and large sample sizes to obtain sufficient power to find underlying genes. In addition, candidate gene studies based on function or position are complementary strategies in a comprehensive approach to understanding the molecular genetic basis of autism. The goals of this project are to localize disease genes in autism through a systematic genome search and candidate gene analysis. In a multi-site international collaborative effort, 240 families with affected sibling pairs with autism will be collected and genotyped on highly polymorphic markers spanning the human genome at regular, close intervals. The U.S. collaborative group will identify and phenotype 120 families with affected siblings with autism and send blood from the families to U.K. for transformation of cell lines. The U.K.-European group of collaborators, through their own funding resources, will collect an additional set of 120 relative pairs and genotyping efforts will be conducted in an independent laboratory facility. Through this international effort susceptibility genes can be identified in approximately 240 pairs. In addition candidate genes will be studied using the transmission/disequilibrium test for serotonergic. dopaminergic. GABAergic and associated disease candidates (tuberculous sclerosis). Linkage disequilibrium studies, conducted in 350 families with only one child with autism and 80 families with a child with Asperger's disorder will allow determination of whether there arc different susceptibility genes involved in simplex autism, multiplex autism, or Asperger's disorder. Once susceptibility genes for autism are identified, their role in the clinical variability in autism and in the expression of putative milder variants in autism, including social functioning deficits, mood, and anxiety disorders may be identified. In addition, identification of the genetic determinants in autism would lay the groundwork for development of improved treatment interventions targeting the pathophysiology of autism.